This invention relates to the field of treating Parkinson's Disease (also termed parkinsonism). Specifically, this invention relates to the treatment of mammals suffering from parkinsonism which comprises administering to said mammal a synergistic amount of a forebrain selective N-methyl-D-aspartate (hereinafter NMDA) antagonist and a compound capable of increasing the excitatory feedback from the ventral lateral nucleus of the thalamus into the cortex, such that the balance of the excitatory feedback from the ventral lateral nucleus of the thalamus into the cortex in said mammal suffering from Parkinson's Disease is restored.
Parkinsonism is an insidious disease characterized by symptoms including progressive tremor, bradykinesia and rigidity. The disease can be fatal within 5-10 years of the onset of symptoms. The underlying cause of Parkinson's disease is the degeneration of the dopaminergic neurons in the nigrostriatal pathway. These dopaminergic neurons are part of a neuronal feedback circuit for the control of motor function. The degeneration of these neurons results in toxic changes in the activity of several of the neuronal pathways in this motor circuit. The outcome of these changes is a significant decrease in feedback from the ventrolateral thalamus to the premotor cortex. This loss of feedback engenders the motor symptoms of the disease.
The only successful treatment for parkinsonism to date is levodopa therapy. Levodopa is a dopamine precursor. Therapy with this agent partially restores the loss of dopamine in the striatum which results from the degeneration of the nigrostriatal dopaminergic neurons. The use of levodopa has greatly improved the quality of life and the life expectancy of patients suffering from parkinsonism. However, the use of levodopa to treat parkinsonism suffers from drawbacks. Levodopa is now most often administered with a levodopa decarboxylase inhibitor such as carbidopa or benserazide. This prevents the conversion of levodopa into dopamine outside of the central nervous system and further improves the benefit/adverse effect ratio of this therapy. Nonetheless, levodopa therapy treats only the symptoms of the disease and does not slow or avert disease progression. Further, the beneficial effects of levodopa therapy on the motor symptoms of the disease decline within several years of beginning treatment. This reduced efficacy is also often accompanied by development of severe dyskinesias and levodopa-induced confusion, hallucinations, paranoia and delirium. Clearly there is a need for a new therapeutic strategy which provides enhanced treatment of the symptoms of parkinsonism and at the same time reduces the side effects which limit the current therapy.
Other approaches are under consideration to treat Parkinson's disease. Some of these approaches aim to replace the loss in dopamine function in the striatum. These include: dopamine receptor agonists including dopamine D1 receptor agonists, dopamine D2 receptor agonists, dopamine D5 receptor agonists, and dopamine/opiate receptor agonists; dopamine uptake inhibitors; tyrosine hydroxylase stimulants; monoamine oxidase inhibitors and monoamine oxidase-B inhibitors; and COMT inhibitors. Still other therapies under consideration are directed at restoring the feedback from the ventrolateral thalamus to the premotor cortex by a variety of mechanisms. These include: AMPA antagonists, GABA agonists, aminergic receptor agonists, muscarinic receptor antagonists, adenosine regulating agents, opiate receptor antagonists, LDH stimulants, CCK receptor agonists, CCK receptor antagonists, adrenoreceptor agonists, IL-1 antagonists, growth factors, antiinflammatory agents, antioxidants, immunostimulants, serotonin reuptake inhibitors, and aminergic reuptake inhibitors. However, while some of these approaches show promise based on animal studies, none of these treatments have yet proved effective in Parkinson' disease in man.
Chenard, in U.S. Pat. Nos. 5,185,343; 5,272,160 and 5,338,754, all three of which are incorporated herein by reference, discloses that compounds of the formulae ##STR1##
are NMDA antagonists and as such have utility in the treatment of Parkinson's Disease.
Butler, in U.S. Pat. No. 5,356,905, also incorporated herein by reference, discloses that compounds of the formula ##STR2##
are NMDA antagonists and as such have utility in the treatment of Parkinson's Disease.
The NMDA antagonists disclosed by Butler and Chenard, when tested in the screen disclosed in Williams et al., Neuron, 10, 267-278 (1993) are shown to be NR2B subtype selective NMDA antagonists. Those skilled in the art are well aware that the terminology "NR2A", "NR2B", "NR2C" and "NR2D" is used to describe NMDA receptors in the rat and that similar receptors exist in other mammals, including humans, which are named differently.
The present invention teaches that forebrain selective NMDA antagonists which are selective for receptors containing the NR2B subunit also act synergistically with levodopa to reverse motor deficits in animal models of Parkinson's disease. The NMDA receptor is comprised of an NR1 subunit in combination with one or more of an NR2 subunits, NR2A, NR2B, NR2C, or NR2D. (Monyer et al., Science, 256, 1217-1221 (1992)). An NR2B selective NMDA antagonist is an agent which has been found to inhibit NMDA receptor function for receptors containing the NR2B subunit but is less efficacious at NMDA receptors which lack this subunit. To date, only non-selective NMDA antagonists have been reported to act synergistically with levodopa in animal models of Parkinsonism. Examples of non-selective NMDA antagonists are MK801, CGS-19,755, or CNS-1102. The present invention teaches that it is the NR2B-containing NMDA receptors which is an important site of action of the non-selective agents.
The adverse effects exhibited upon administration of certain NMDA antagonists are not observed or are significantly reduced when using the forebrain selective NMDA antagonists of the instant invention. Thus, the present invention allows the utilization of the full therapeutic potential of levodopa by using NMDA antagonists synergistically in combination therewith.